Amyloid Beta
38-43 amino acids in length derived from APP through endoproteolytics cleavages Synthesis of A-beta precursor APP synthesised in... cleavage by secretase-alpha A-beta metabolism CNS-specific proteolytic events. how is A-B metabolism regulated Pathogenesis associated with AD and CAA Treatment Intracerebral administration of a lentivirus expressing human apoE2 into the brains of PDAPP mice has shown that gene delivery strategies may be useful in decreasing Aβ burden (Dodart et al., 2005). Seeds of despair? http://onlinelibrary.wiley.com/doi/10.1002/ana.22615/full The ability of Aβ-rich brain extracts injected into the peritoneal cavity to induce Aβ deposition in the brain56 indicates that Aβ seeds resemble prions in their ability to reach the central nervous system from the periphery. In the absence of direct evidence linking nonprion neurodegenerative diseases to seeds arising outside the central nervous system or taken up from the environment (eg, in food or air), the practical implications of this finding are uncertain. It is probable, however, that a fuller understanding of the trafficking of pathogenic seeds will yield insights into the endogenous progression of disease, and hence denote novel points of intervention. For example, the early appearance of α-synuclein–containing Lewy bodies in the peripheral nervous system, and their relatively systematic spread within the brain,98, 99 suggest that seeds in transit (ie, those traveling between cells or from one region to another) might be profitable objectives for therapeutic interference.44 Experimentally, Aβ induction can be triggered in transgenic mice by intracerebrally implanted stainless steel wires coated with minute amounts of brain extract rich in aggregated Aβ . 2011 Oct http://www.ncbi.nlm.nih.gov/pubmed/22028219/ Experimentally, cerebral β-amyloidosis can be exogenously induced by exposure to dilute brain extracts containing aggregated Aβ seeds. http://www.ncbi.nlm.nih.gov/books/NBK6203/#A15241 Potential Role of Endogenous and Exogenous Ab Binding Molecules in Ab Clearance and Metabolism 2000 are derived from the amyloid precursor protein (APP) through a series of endoproteolytic cleavages. normally soluble Ab peptide into forms with high β-sheet content appears to be central to the pathogenesis of Alzheimer's disease (AD) Genetic and biochemical evidence supporting this idea is that all known mutations that cause early-onset forms of familial AD or Ab-related cerebral amyloid angiopathy (CAA) map to three genes (APP, presenilin 1 (PS1), and presenilin 2 (PS2)). Further, all individuals with Down syndrome possess three copies of APP, have increased levels of Ab,3 and all develop AD pathology by age 35.4 However, it must be remembered that the familial mutations in humans that lead to the increased synthesis of Ab account for less than 1% of the total cases of AD. Although studying Ab metabolism post genesis is difficult, it is of paramount importance when considering that >99% of all AD cases result independently from genes known to increase Ab synthesis Numerous in vitro biochemical studies demonstrated isoform-specific effects of ApoE on binding to the Ab peptide, altering Ab toxicity, and modulating the propensity of the Ab peptide to aggregate (for review, see refs. 61). Additionally, in vitro studies suggest that ApoE can mediate Ab clearance by lipoprotein receptor-mediated endocytosis.62,63 What was unclear, however, from these studies was whether any of these in vitro findings had physiological relevance in vivo. http://www.ncbi.nlm.nih.gov/pubmed/18438935 Swedish amyloid precursor protein mutation increases cell cycle-related proteins in vitro and in vivo. https://www.thieme-connect.de/DOI/DOI?10.1055/s-2003-43059 Cholesterol Modulates Amyloid Beta-peptide's Membrane Interactions Abstract The causal relationship between amyloid beta-peptide (Aβ) deposition and Alzheimer's disease (AD)-specific neuropathological lesions such as neurodegeneration and cortical atrophy is still not known. Mounting evidence points to alterations in cholesterol homeostasis occurring in AD brain that are probably linked to cerebral Aβ pathology. Interestingly, cholesterol not only modulates Aβ synthesis, but also controls interactions between Aβ and neuronal membranes that are regarded as decisive in the initiation of a neurotoxic cascade. This review focuses on the impact of cholesterol on membrane disordering effects of Aβ. Cholesterol is known to be an essential modulator of physicochemical state and functional activity in physiological membranes, and thus plays an essential role in the regulation of synaptic function and cell plasticity. In vitroand in vivo modulation of membrane cholesterol levels affect different cholesterol pools within the plasma membrane bilayer that are differentially sensitive to Aβ's disrupting effects. Membrane acyl-chains in the hydrocarbon core are most susceptible to Aβ. In this membrane region, cholesterol attenuates the membrane disordering effects of Aβ. This cholesterol pool is modulated by methyl-beta-cyclodextrin (MβCD) treatment in vitro. On the other hand, statin treatment in vivo depletes a cholesterol pool in a membrane area, which is much less susceptible to Aβ's membrane-disrupting effects. Our findings clearly implicate an involvement of cholesterol in brain membrane alterations occurring during AD. Disease-related changes in membrane cholesterol metabolism may be subtle and restricted to defined membrane pools since total membrane cholesterol levels are mainly unchanged in AD brain. Thus, elucidation of the structure and function of different cholesterol pools is necessary in understanding the coherence between cholesterol and AD. Category:neurodegenerative disease